Cyclization, of hydroxy aldehyde

All hemiacetals are formed by nucleophilic addition of a hydroxy group to a carbonyl group. In the same way, cyclic hemiacetals are formed by intramolecular cyclization of hydroxy aldehydes. 

Hemiacetals in sugars are formed in the same way that other hemiacetals are formed—that is. by cyclization of hydroxy aldehydes. Thus, the hemiacetal of glucose is formed by cyclization of an acyclic po/yhydroxy aldehyde (A), as shown in the accompanying equation. This process illustrates two important features. 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

Cyclizations of hydroxy esters under basic conditions have been achieved." Aldol reactions of a-keto esters with aldehydes give unsaturated lactones." The photocatalytic addition of alcohols 17 to a,/f-unsaturated acids (e.g., 18) or esters is an example of a radical... 

DCC-mediated condensation of hydroxy aldehyde 240 and acid 268 gave the aldehyde ester 269 (70%). An intramolecular olefination followed by chromatographic separation of the desired C-8 diastereomer led to the isolation of the 16-membered ring macrocycle 270 in 20% yield. Desilylation, oxidation, and cyclization then afforded a 47% yield of y-lactone 271. Acylation of the C-3 hydroxyl group was followed by reduction of the y-lactone and C-9 carbonyl. 

Chlorosulphonyl isocyanate (reviews [324, 3147a, 3340] cyclizes 2-hydroxy-aldehydes and -acetophenones in good yields the corresponding benzophenones are not cyclized in this way. Methyl isocyanate in alkaline solution also reacts with salicylaldehyde to give a high yield of a fused oxazinone. 

Reaction of 2-chloro 3-substituted quinoxalines 22 with hydrazines provides another simple preparation of pyrazolo[3,4-h]quinoxalines. The parent heterocycle 23 has been obtained by treating the aldehyde 22 (R = CHO) or the dibromomethyl derivative 22 (R = CHBr2) with hydrazine. Similarly the nitrile 22 (R = CN) has given the 3-amino compound 24 in 72% yield, and methylhydrazine with the ester 22 (R = COjEt) gave the 3-hydroxy derivative 25. In spite of the ready cyclization of the aldehyde 22 (R = CHO) with hydrazine, the corresponding... 

Condensation of 4,6-dimethoxy-2-hydroxyacetophenone with diethyl carbonate and an alkoxide ion has now been shown to give the coumarin-3-carboxylic ester (245), and not 4-hydroxy-5,7-dimethoxycoumarin (246), as originally reported. Heating the ester with aqueous alkali resulted in hydrolysis and decarboxylation to (246). The well-established acid cyclization of salicyl-aldehyde with ethyl cyanoacetate to give coumarin-3-carboxylic acids has been studied in alkaline media and found to give the ester (247 X = O) and the imino-ester (247 X = NH). When the proportion of the cyano-ester was increased, high yields of the latter were obtained. "... 

Hydroxy-di- and -tetra-hydropyridines (337), potentially useful heterocyclic intermediates, have been prepared by an acid-catalysed cyclization of unsaturated aldehydes (335 ). In the dihydro-series the chloride (336) is sufficiently stable to allow isolation but the tetrahydro-derivative undergoes hydrolysis on attempted chromatography to give (337). 

Anthracyclinones of the rhodomycinone type (type A) can efficiently be synthesized by Marschalk reaction of -hydroxy aldehydes 1. Both diastereoisomeric cyclization products 2 and 3 are obtained in aqueous-methanolic reaction medium but the natural configuration 2 is formed almost exclusively under phase transfer conditions. 

Unusual 2 + 1-adducts of citronellal (103) and oligo(hydroxy)benzenes are formed via acid-catalysed condensation, apparently via cyclization of the aldehyde, and subsequent carbocation formation via loss of hydroxide. ... 

The intramolecular cyclization of diketo-enals and keto-enals was accomplished by the combination of a cationic Rh complex and fn(2-furyl)phos-phine (2 - Fur3P). The corresponding bicyclic hydroxy-aldehydes were produced in good to excellent yields, as demonstrated by the formation of 74,76 and 78 (Scheme 22) [36]. 

It is well known that in the cyclization of a y-hydroxy aldehyde to form the corresponding six-membered ring hemiacetal through intramolecular cyclization the hemiacetal form always predominates (48). This might account for the fact that no noticeable carbonyl absorption has been observed in the IR and NMR spectra of 54. However, the equilibrium between the hemiacetal and the aldehyde forms might shift in favor of the aldehyde form as the borane reduction proceeds until 54 is completely transformed to 55. 

Yet another approach to the synthesis of five-membered cyclic nitronates (5) is based on the Henry condensation of a-halo-substituted aldehydes (9) with primary AN followed by cyclization of nitroaldols (Scheme 3.14, Eq. 4) to give five-membered nitronates containing the hydroxy group at the C-4 atom. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

The a-silyloxy alkyl radical generated by the addition of (TMS)3Si radical to the aldehyde moiety of 45 has been employed in radical cyclization of (3-aminoacrylates (Reaction 7.53) the trans-hydroxy ester and the lactone in a 2.4 1 ratio were the two products [62]. 

The cyclization of A-substituted-2-hydroxy-l-carboxamides with aldehydes and ketones has been successfully performed only in the case of N-methyl derivatives. Under similar conditions, the unchanged starting material was recovered from the reactions of other A-substituted-carboxamides (A-substituent = Ph, CH2Ph or CH2CH2Ph) [84JCS (Pl)2043]. 

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